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Cadherins are a family of glycoproteins that are associated with cell adhesion mechanisms. They are divided into subclasses. The E- and P-cadherins are regarded as the epithelial subtype. Their expression has been demonstrated in many different carcinoma types. Using immunomorphological techniques, we studied the expression of E-cadherin in a series of 145 human brain tumours with the monoclonal antibody 5H9. Western blot analysis was used to confirm the immunohistochemical data. The tumour types represented were astrocytoma WHO I (n = 7), astrocytoma WHO II (n = 6), astrocytoma WHO III (n = 14), glioblastoma WHO IV (n = 8), oligodendroglioma WHO II (n = 5), ependymoma WHO II (n = 5), choroid plexus papilloma WHO I (n = 5), pineoblastoma WHO IV (n = 5), medulloblastoma WHO IV (n = 5), neurinoma WHO I (n = 5), meningioma WHO I and WHO III (n = 75) and pituitary adenoma WHO I (n = 5). Only choroid plexus papillomas (5/5) and meningiomas showed E-cadherin expression. In benign meningiomas (n = 45; 100%), positive E-cadherin immunoreactivity was found regardless of the histomorphological subtype. E-Cadherin was also expressed in 21 WHO I meningiomas (100%) invading dura, bone, brain, and muscle. In contrast, E-cadherin was absent from the majority of morphologically malignant meningiomas (6/9, 66.6%). In addition, in recurrent meningiomas (n = 9), E-cadherin expression in the recurrent tumours was identical to that in the primary neoplasm except in cases with malignant progression, where the malignant recurrent tumour was E-cadherin negative. In 2 cases of metastasizing meningiomas, no E-cadherin immunoreactivity was found in the primary tumours or their metastases.

Giant cell glioblastoma is a rare glioblastoma variant characterized by the presence of large, bizarre, multinucleated giant cells. This glioblastoma subtype develops clinically de novo after a short clinical history and contains a high frequency of p53 mutations. In this study, we screened a series of 18 giant cell glioblastomas for additional genetic alterations. PCR-SSCP followed by DNA sequencing revealed PTEN mutations in 5 of 15 tumors (33%). Of these, two mutations were located in exon 5, two mutations in exon 6, and one mutation each in exons 1 and 9. Four mutations were point mutations and two mutations were deletions. One neoplasm contained two PTEN mutations (exons 5 and 6). None of the giant cell glioblastomas showed a homozygous deletion of PTEN orp16, or amplification of MDM2. Immunohistochemically, MDM2 overexpression was either not observed or detected in only a minor fraction of tumor cells. Differential PCR revealed EGFR amplification in only one of 17 tumors (6%). These results indicate that giant cell glioblastomas occupy a hybrid position, sharing with primary (de novo) glioblastomas a short clinical history, the absence of a less malignant precursor lesion and a 30% frequency of PTEN mutations. With secondary glioblastomas that develop through progression from low-grade astrocytomas, they have in common a younger patient age at manifestation and a high frequency (70%) of p53 mutations.

The clinical, histological and immunomorphological data in 19 cases of primary spinal epidural manifestation of malignant lymphomas collected between 1974 and 1994 are reported. The age of the patients varied between 11 and 87 years with a mean age of 56.3 years. There was a slight male predominance (11:8). In most cases, the onset of the clinical symptoms was rapid. The preferential tumour localization was the epidural space related to the thoracal vertebral bone. In each case, decompressive laminectomy was performed. The tumours were histologically and immunomorphologically classified as B-cell lymphomas (14 of 19), T-cell lymphomas (3 of 19) and anaplastic plasmacytoma (1 of 19). Except for one case, post-operative staging did not reveal anything other than epidural manifestation of the malignant lymphoma. The vertebral bone, however, was involved in seven cases. Irradiation alone, or in combination with chemotherapy, was performed as additional therapy. The post-operative survival time was variable.

We report on three patients who presented with a cerebellar medulloblastoma at age 48, 53, and 59 years. Histopathology showed typical features of medulloblastoma, in one case with marked neuronal differentiation. In addition, all neoplasms contained focal accumulations of mature fat cells. Immunoreactivity of adipocytes for S-100 protein, neuron-specific enolase, synaptophysin, microtubule-associated protein-2, and glial fibrillary acidic protein and the lack of immunoreactivity to type IV collagen suggest lipomatous differentiation of neoplastic primitive neuroectodermal cells rather than an admixture of mesenchymal elements. Mitotic activity was low and the growth fraction, as determined by the MIB-I labeling index, was less than 5%. All patients are alive with a recurrence-free interval ranging from 3.5 to 12 years. These three patients and five similar previously reported cases all fit into the concept of the lipomatous medulloblastoma as a new clinicopathological entity characterized by (a) typical features of a cerebellar medulloblastoma with advanced neuronal differentiation, (b) areas of lipomatous differentiation, (c) low proliferative potential, (d) manifestation in adults (mean age, 50 years), and (e) apparent favorable clinical prognosis.

Since 1972 organ transplantations of kidney, bone marrow, liver, heart and lung have been performed at the University Hospital of Essen, Germany. Out of 2535 transplantations until September 1993, autopsies were performed in 157 patients In 25 patients (15.9%) neuropathologic findings (n = 26) were found. In 97 autopsies after bone marrow transplantation, 9 patients (9.3%) exhibited a severe neuropathologic alteration. In six patients (6/9; 66.6%), necrotisizing toxoplasmose encephalitis was found. Other cases showed a septic-metastatic mycotic encephalitis with crypto-coccus neoformans and candida albicans (n = 2) and leucemia infiltrates (n = 1). Massive cerebral hemorrhage was the most frequent neuropathologic finding after liver (4/8) and kidney transplantation (3/6). In addition liver-transplanted patients exhibited septic-metastatic encephalitis (3/8) and embolic brain infarct (1/8) as well as cerebral metastases (2/6) and primary malignant cerebral lymphoma in kidney transplantation (1/6). CNS findings in five autopsies after heart-lung-transplantation were diverse. They comprised intracerebral hemorrhage, intravasal lymphoma and septic-metastatic encephalitis, respectively. In summary, neuropathologic autopsy findings after organ transplantation are diverse and preferentially comprise infections, cerebral hemorrhages, and malignant lymphomas. After bone marrow transplantation, the most frequent neuropathologic autopsy finding was toxoplasmose encephalitis and massive cerebral hemorrhages after liver and kidney transplantations.

Most likely identical to ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCH-L1), protein gene product (PGP) 9.5 is one of the major constituents of cytoplasmic polypeptides in neurons. The antigen seems to be expressed almost exclusively in neuronal and neuroendocrine tissues and their neoplasms. PGP 9.5 is also present in undifferentiated embryonic neoplasms like primitive neuroectodermal tumors (PNETs). However, the significance of PGP 9.5 as a marker in diagnostic (neuro-) oncology has not been systematically evaluated yet. In the present study the sensitivity and specificity of the widely used antiserum against PGP 9.5 has been retrospectively examined on 290 formalin-fixed, paraffin-embedded tumors of the nervous system and small round blue cell tumors. The presence of the antigen in tumors of neuronal (24/24) and neuroendocrine (63/73) differentiation confirm PGP 9.5 as a sensitive marker of these tumor groups, particularly in the diagnosis of pituitary adenomas where the expression was neither related to the staining behavior of the tumors in the PAS-orange G-reaction nor to their degree of polypeptide- and glycoprotein hormone activity. The nearly constant immunostaining of medulloblastomas (18/19) and other PNETs (5/6) demonstrate the role of PGP 9.5 as an additional marker in the detection of these embryonic tumors as this peptide was not or only weakly found in glial (11/58), meningeal (5/29), and nerve sheath neoplasms (1/28). On the other hand, the significance in the differential diagnosis of small round blue cell tumors seems to be limited because of positive immunoreactions in neuroblastomas (7/7) and oat cell carcinomas of the lung (7/7) although rhabdomyosarcomas (1/6) and malignant Non-Hodgkin-lymphomas (0/13) react completely negative in our series.

The monoclonal antibody HMB45 is used to detect an epitope specific for melanocytes, malignant melanomas and melanoma metastases. Using the PAP method, we observed consistent expression of HMB45 in 19 metastases of melanotic and amelanotic malignant melanomas of the central nervous system, while metastases of 32 adenocarcinomas, 10 squamous cell and 8 small cell carcinomas were negative except for 2 cases of breast cancer. Differential diagnosis between cancer and melanoma metastases can be made using cytokeratins as an additional immunocytochemical marker protein. Ten meningeomas and 5 pineocytomas were also negative. Even though it is not absolutely specific, we consider the HMB45 immunoreaction diagnostic for a metastasis of a malignant melanoma if the tumour is cytokeratin negative and HMB45 positive in a large number of tumour cells.

The development of human cancer is a multistep process that entails a progressively more malignant phenotype through the evolution of cellular subsets with increasing numbers of genetic alterations. Here we review the molecular genetics of human cancer predisposition and progression and describe paradigmatic cancer types and cancer syndromes. We also briefly consider the future impact of molecular biology on cancer diagnosis and treatment.

Meningioma is a common tumor of the central nervous system which displays morphological heterogeneity. In order to determine whether this phenotypic variability is associated with distinct or overlapping genetic lesions, we compared genotypes at several loci defined by allele length polymorphism in tumor and normal tissues from patients with meningioma. In particular, we concentrated on loci on chromosomes 22 and 10 because these genomic regions have previously been shown to be altered in the former in sporadic and familial meningiomas and in the latter as a late stage event in progression of another common brain tumor, astrocytoma. We examined 38 tumors which were classified as benign, atypical, or malignant by morphological criteria, invasive characteristics, or both. We found that loss of heterozygosity (LOH) for loci on chromosome 22 occurred in 5 of 15 benign, 2 of 2 atypical, and 5 of 10 malignant meningiomas. Similar alterations of chromosome 10 were found in 0 of 20 benign, 1 of 2 atypical, and 4 of 13 malignant meningiomas. Among the malignant tumors, LOH for loci on chromosome 10 occurred in 2 of 4 morphologically malignant tumors and in 2 of 4 morphologically and invasively malignant tumors. In contrast, LOH was not observed for any of the 5 informative tumors classified as malignant by invasive characteristics only. LOH for loci on chromosome 22 accompanied (but was not restricted to) allelic loss of loci on chromosome 10. These data suggest that the progression of meningiomas from arachnoidal cells to the morphologically malignant phenotype may, in part, entail the loss of a tumor suppressor gene(s) on chromosome 22 early in the process and that this may be compounded by alterations of chromosome 10, the LOH of which is associated with morphological signs of malignancy.

The case history is presented of a man who died at the age of 38 years and had been suffering from severe torsion dystonia and a hypokinetic-rigid motor disturbance since the age of 10. The pathological findings were isolated pallidal degeneration with demyelination and moderate neuronal loss, iron pigment accumulation and spheroid bodies in both pallidal nuclei. In addition the zona reticularis of the substantia nigra was hypoplastic and not affected. The red nucleus, the dentate nucleus and the zona reticularis of the substantia nigra showed iron depigmentation. The rare condition of non-familial Hallervorden-Spatz syndrome, without involvement of the zona reticularis and the cerebral cortex, was considered to be the diagnosis.

Synaptophysin is an acidic, integral membrane glycoprotein (Mr 38,000) of presynaptic vesicles in various neurons and neuroendocrine cells, and in tumours derived from such cells. By indirect immunofluorescence microscopy of cryostat sections, using the monoclonal antibody SY 38 to synaptophysin, a consistent positive immunoreactivity was observed in all medulloblastomas (n = 6) and neuroblastomas (n = 3) as well as a ganglioneuroma and a glioneuronal hamartoma. The presence of synaptophysin in medulloblastomas was confirmed biochemically by immunoblotting experiments. For purpose of comparison, the expression of intermediate-sized filament (IF) proteins was also examined. While neurofilament proteins were consistently expressed in the neuroblastomas (3/3), the ganglioneuroma and the glioneuronal hamartoma, IF distribution in medulloblastomas was variable. A neurofilament-positive type of tumour (1/6) could be distinguished from vimentin-expressing neoplasms (4/6) by immunocytochemistry. These data indicate that synaptophysin is a reliable marker for medulloblastomas as well as other differentiated and undifferentiated neuronal tumours and in this respect is superior to the more heterogeneous expression patterns of IF proteins in these tumours.

Using a lectin-peroxidase method, Concanavalin A binding was examined on formalin-fixed paraffin-embedded biopsy specimens (n = 143) of the most frequent central nervous system tumours. The brain tumours included oligodendrogliomas, astrocytomas, glioblastomas, ependymomas, neurinomas, meningiomas, medulloblastomas and plexus papillomas. In oligodendroglioma cells, only a weak granular intracytoplasmic staining was observed. The astrocytomas showed a strong reaction in fibrillary astrocytes and in tumour areas undergoing small cystic degeneration. Staining of protoplasmic astrocytes was weaker; pilocytic astrocytes demonstrated poor perinuclear staining. Intracytoplasmic Con A binding in gemistocytic astrocytes was distinct but inconstant and rather diffuse. In the glioblastomas the lymphocyte-like small astrocytes were negative. Giant multinucleated astrocytes stained strongly. In ependymomas no or at most a weak perinuclear reaction was observed, whereas the acceptor density was as high as in the normal ependymocytes in areas where the tumour was capable of producing organotypical structures. Plexus papillomas showed a strong intracytoplasmic staining comparable to the normal plexus epithelial cell. This feature was preserved in the malignant variants. In general, meningiomas and neurinomas were negative. Xanthomatous-degenerated meningioma cells, however, showed a distinct to strong intracytoplasmic staining. This feature was characteristic for the xanthomatous subtype of meningiomas. Granular cells with strong intracytoplasmic Con A staining often occurred at the border of fibrillary to reticular differentiated areas of neurinomas. Medulloblastomas were completely negative. Our results indicate that Con A binding to human brain tumours is specific and rather cytotypical than histotypical. The Con A acceptor density is probably related to the grade of differentiation. Lectin mapping of tumours leads to cytotypical binding patterns which may contribute to the differential diagnosis of neoplasias.

Twenty-seven human low and high grade gliomas and five meningiomas were cultured in vitro as tumour tissue and/or tumour cells. Cell survival or growth was taken as a measure of radiation response. Astrocytomas II-III and glioblastomas manifested individual patterns of radiosensitivity, ranging from 10 to 90 Gy. Meningiomas did not react. Our findings are consistent with the differences in radiosensitivity of human gliomas experienced clinically and corroborate the validity of the in vitro model.

Human gliomas were grown as permanent tissue cultures and xenografts in nude mice. Growth kinetics, immunohistology and karyotypes were established. One tumor showed a distinct change in its karyotype after only two passages in nude mice; by contrast, no change of immunophenotype occurred during and after in vivo passaging. Treatment of this glioma as xenograft in nude mice revealed a high sensitivity towards single agent treatment with BCNU. In view of the cytologic aberrations, however, this result should be interpreted cautiously with regard to the clinical situation.

Peanut lectin (PNL) binding to a total of 13 granular cell tumours was examined by means of the peroxidase antiperoxidase technique. The tumours included six tumourettes of the neurohypophysis, one malignant granular cell tumour of the brain, and six peripheral tumours of distinct locations. Every tumour studied showed intracytoplasmic fine granular PNL binding; after pretreatment with neuraminidase, the weakly positive reaction was enhanced to a great extent. In all tumours simultaneous examination for the detection of lysozyme and glial fibrillary acidic protein (GFAP) was also carried out. Lysozyme was negative in all cases, whereas GFAP expression could be demonstrated at the periphery of the malignant granular cell tumour of the brain. The data presented clearly demonstrate that PNL can be used as a histochemical marker for granular cells regardless of their location. The fact that the presence of lysozyme could not be proved does not support the view of a histiocytic origin for granular cells, whereas the expression of GFAP in some immature granular cells of the brain tumour examined is considered to be an argument in favor of its glial origin.

Desmosomal proteins are co-expressed with intermediate-sized filaments (IF) of the cytokeratin type in epithelial cells, and these IF are firmly attached to the desmosomal plaque. In meningiomal and certain arachnoidal cells, however, vimentin IF are attached to desmosomal plaques. Meningiomas obtained after surgery, arachnoid "membranes", and arachnoid granulations at autopsy, as well as meningiomal cells grown in short-term culture have been examined by single and double immunofluorescence and immunoelectron microscopy using antibodies to desmoplakins, vimentin, cytokeratins, glial filament protein, neurofilament protein, and procollagen. In addition, two-dimensional gel electrophoresis of the cytoskeletal proteins has been performed. Using all of these techniques, vimentin was the only IF protein that was detected in significant amounts. The junctions morphologically resembling desmosomes of epithelial cells have been identified as true desmosomes by antibodies specific for desmoplakins and they provided the membrane attachment sites for the vimentin IF. These findings show that anchorage of IF to the cell surface at desmosomal plaques is not restricted to cytokeratin IF as in epithelial cells and desmin IF as in cardiac myocytes, suggesting that binding to desmosomes and hemidesmosomes is a more common feature of IF organization. The co-expression of desmosomal proteins and IF of the vimentin type only defines a new class of cell ("desmofibrocyte") and may also provide an important histodiagnostic criterion.

In order to determine the effect of routine fixation on the lectin affinity of tissue structures, we used unconjugated lectins and an indirect immunoalkaline-phosphatase method for frozen sections, and the peroxidase-anti-peroxidase method for paraffin-embedded, formalin-fixed tissue sections. Fourteen hyperplastic human tonsils were used, and the results of the binding spectra of each lectin were compared. In general, the binding spectrum detected in the paraffin sections was part of the broader range of affinity obtained in the frozen sections. The lectin receptors on the cell surface were especially affected by formalin fixation. On the other hand, the paraffin sections, because of their superior morphology, showed a better localization of the cytoplasmic reaction product and discriminated the cell types more accurately. Thus, the two tissue preparations are rather complementary. In the tonsil peanut agglutinin (PNA) and periodic acid/Concanavalin A (PA/Con A) proved to be suitable tools for distinguishing exactly between the crypt and the surface epithelium. Ulex europaeus agglutinin I (UEA) is a reliable endothelial marker with a strong affinity to the crypt epithelium. In the frozen sections, PNA regularly stained follicular-centre cells on their cell surface. PNA, Helix pomatia agglutinin (HPA), soybean agglutinin (SBA) and Con A stained the histiocytic population, especially PNA which additionally stained an "asteroid" histiocyte. This cell probably corresponds to the antigen-presenting histiocyte of the T-system.

The expression of intermediate-sized filaments (IF) was examined by immunocytochemical methods in 40 primary renal cell carcinomas and compared with the IF distribution in the normal adult human kidney. All tumours stained positively with cytokeratin IF antibodies. Co-expression of cytokeratins and vimentin was observed in 21/40 (52,5%) renal carcinomas. Double immunofluorescence labelling demonstrated that in most of these cases tumour cells contained both cytokeratin and vimentin type IF. In normal human kidneys, cells of the various tubular segments disclosed a positive reaction with cytokeratin antibodies in a different intensity and intracellular localization. Co-expression of cytokeratin and vimentin IF in normal adult human kidneys has never been observed. From a histogenetic point of view, co-expression of cytokeratins and vimentin in renal cell carcinoma obviously represents an atavistic phenomenon since vimentin is re-expressed by these tumour cells during neoplastic transformation. This finding indicates the metanephric origin of the renal parenchyma. In surgical pathology the possibility of very rare co-expression of cytokeratin and vimentin IF within tumour cells should be considered, particularly in the differential diagnosis of clear cell carcinomas.

Peanut lectin (PNL), Concanavalin A (Con A) and Ulex europaeus lectin I (Ulex) were chosen to map their binding sites in different regions of formalin fixed and paraffin embedded human central nervous system tissue and pituitary gland tissues. An extended PaP method was used for PNL and Ulex, whereas a direct peroxidase technique was employed for Con A. In astrocytes, the cytoplasm as well as the delicate processes were stained by PNL and Con A; the most conspicuous binding of PNL was seen in the ependymal cells and on the surface of plexus epithelial cells; in the anterior part of the pituitary gland a selective population was PNL positive. Intracytoplasmic Con A acceptors could be demonstrated in neurons, in ependymal cells, and in plexus epithelial cells. Intracytoplasmic Con A receptors were finely granular in astrocytes, oligodendrocytes, and in some cells in the pituitary gland. Ulex binding was restricted to the vascular endothelial cells and a selective population of cells in the pituitary gland. Our results suggest that lectins may be good tools for the evaluation of their respective target cells in the central nervous system and in the pituitary gland.

Synaptophysin is an integral membrane glycoprotein originally isolated from presynaptic vesicles of bovine neurons. The authors have studied a wide spectrum of neuroendocrine (NE) neoplasms by immunofluorescence microscopy on cryostat sections of freshly frozen tissues using a monoclonal antibody to this protein (SY 38). Without exception, they found the identical--or a very similar--protein expressed in all neuroblastomas, ganglioneuroblastomas, ganglioneuromas, pheochromocytomas, and paragangliomas studied. In these "neural" type NE neoplasms, synaptophysin was coexpressed with neurofilament proteins. Synaptophysin was also demonstrated in NE neoplasms of "epithelial" type in which it was predominantly coexpressed with cytokeratins and desmoplakin. It was invariably found in all variants of islet cell neoplasms and in all medullary thyroid carcinomas. Synaptophysin was also demonstrated in several adenomas of the hypophysis and parathyroids, in the majority of carcinoids of the bronchopulmonary and gastrointestinal tracts, and in many, though not all, NE carcinomas of the same sites, and of the skin. Conversely, SY 38 did not immunostain any of a large number of benign and malignant non-NE epithelial neoplasms; nor was any immunostaining obtained in a group of mesenchymal tumors. It is remarkable that SY 38 did not immunostain a number of malignant melanomas, including several that were immunostained for neuron-specific enolase (NSE) and several neuropeptides. Parallel studies conducted on conventionally fixed, paraffin-embedded tissue sections immunostained by the use of the avidin-biotin complex technique yielded very similar results. The findings indicate that synaptophysin is expressed in the whole range of NE neoplasms without detectable relation to the expression of other NE markers such as NSE, serotonin, and neuropeptides. Nor could the expression of synaptophysin by these tumors be correlated with their epithelial and/or neural cytoskeletal characteristics, their clinical aggressiveness, or the presence or absence of endocrinologic abnormalities. While the consistent expression of synaptophysin by the "neural" type of NE neoplasms would seem predictable its presence in diverse benign and malignant NE tumors of "epithelial" type is remarkable. It is concluded that synaptophysin is a significant as well as novel NE marker, and the use of antibody SY 38 as a broad range marker for the study and diagnosis of NE neoplasms is proposed.

The case of a patient with a cauda syndrome without sensory deficits following radiation therapy to the lumbosacral cord is reported. This patient received a total dose of 38 Gy to the lumbar vertebrae because of bone metastases of a carcinoma of the breast. On autopsy, degeneration of cauda equina nerve roots with an irregular distribution was found. Anterior horn neurons showed central chromatolysis. No definite ischemic lesions were detectable. This is the first case report on neuropathological findings in lumbosacral radiation myelopathy.

Ten tumours of tonsillar or epipharyngeal localization showing the histological picture of “lymphoepithelial carcinoma” (Schmincke 1921) were examined immunohistochemically using Peanut lectin, Ulex europaeus lectin-I and an antiserum to S-100 protein. The findings suggest a close relationship of this type of carcinoma to the normal tonsillar crypt epithelium. The majority of tumour cells are UEA-I-positive and PNL-negative, as is the crypt epithelium, while oral mucosa is both PNL- and to a lesser extent UEA-I-reactive. Tumour areas expressing this pattern contain a large number of asteroid-shaped PNL-positive histiocytes and arachnoid-shaped histiocytes reacting with anti-S-100 protein; both cell types being probably identical and representing typical elements of the normal tonsillar crypt epithelium. Consequently, the WHO-term “nasopharyngeal carcinoma, undifferentiated type” seems to be inadequate for this type of tumour.

Ten human meningiomas of different histologic subtypes (endotheliomatous, transitional, fibroblastic, and angioblastic) were examined for the expression of intermediate-sized filaments (IF) and desmosomal plaque proteins (desmoplakins I and II), using immunofluorescence and immunoelectron microscopy. All meningiomas gave a strong positive reaction for vimentin as well as for desmoplakins. IF of the cytokeratin type, desmin IF, and glial filaments were not detected in any of these tumors. The exclusive expression of vimentin in these tumors was confirmed by two-dimensional gel electrophoresis and immunoblot analysis of cytoskeletal proteins obtained after microdissection of well-defined tumor areas. Ultrastructural immunolocalization showed that, in the various tumors, vimentin IF were attached to the desmosomal plaques. With respect to the markers examined, all of the diverse types of meningiomas reacted like their putative non-neoplastic counterparts, i.e., arachnoidal cells. Our results indicate that the different histologic subtypes of meningiomas are derived from cells of the arachnoidal layer. The exclusive expression of vimentin-type IF in combination with desmoplakins is very unusual and so far seems unique to arachnoidal and meningioma cells. We consider this unusual combination, i.e., vimentin IF and desmoplakin plaques, to be a diagnostic feature for meningiomas, and we propose that the cytoskeletal property be used in differential diagnosis of intracranial tumors.

Electron microscopy reveals rough endoplasmic reticulum and other cytoplasmic organelles in the intranuclear spheroids of human arcuate neurons with feedback phenomenon. After peroxidase-antiperoxidase technique was applied some of these arcuate nerve cells demonstrated luteinizing hormone releasing hormone immunoreactivity.

Unilateral exophthalmos was caused by a cholesterol granuloma in a 42-year-old patient. The clinical picture, roentgenographic and NMR tomographic changes, surgical therapy and histopathological results are described and discussed with regard to the etiology and differential diagnosis of this disease.

Peroxidase-antiperoxidase (PAP) technique was selected for visualizing the binding of peanut lectin (PNL) to the most frequent human brain tumors. The randomly selected material included neoplasms of neuroectodermal and mesenchymal origin. We employed 1--5 micrometers of routinely processed and paraffin-embedded tissues. PNL receptors were detected to a variable extent on the cell surface of astrocytoma, glioblastoma multiforme, oligodendroglioma, ependymoma, meningotheliomatous meningeoma, and plexus papilloma. In gliomas as increase in malignancy seems to be associated with a decrease in PNL binding. Except for the plexus papillomas, neuraminidase pretreatment had neither a qualitative nor a quantitative influence on the binding behavior of PNL. Intracellular PNL receptors could be detected in "granular cells" and in the perinuclear region of malignant gliomas.

Intramedullary metastases are very rare. We report four cases verified by autopsy. The site of the primary tumor was the lung (three cases) and the breast (one case). One case was complicated by a Brown-Séquard syndrome. We found 96 cases of intramedullary metastases in the literature. The primary tumor sites were lung (49%), breast (14%), kidney (6%) and colo-rectal region (5%). Melanoma was noted in 6% and Hodgkin's disease in 4% of the cases. Other primary tumors comprised 9%. The intramedullary metastases were most commonly thoracic. We compare our findings to those in the literature.

Rare plasmocytomas without paraprotein (frequency less than 1%) can present a diagnostic trap. Three observations give grounds for drawing attention to misinterpretation of symptoms and the problematic nature of the diagnosis. In one patient, a monoclonal immunoglobulin (kappa light-chains) was detectable in the bone-marrow myeloma cells (non-excretory plasmacytoma). In a further patient no paraprotein could be found in the myeloma cells (non-secretory plasmacytoma) despite repeated investigations. An additional unusual feature in a third patient was the simultaneous presence of chronic lymphocytic leukaemia; his plasmocytoma was first detected at autopsy.

A sensitive immunoenzymatic double-staining technique is presented for the simultaneous visualization of lectin-binding sites and antigenic structures detected by monoclonal antibodies. The lectin is demonstrated by an extended unlabeled peroxidase-antiperoxidase (PAP) technique and the monoclonal antibody by an alkaline phosphatase-antialkaline phosphatase (APAAP) method, which corresponds to the standard PAP technique. 3-amino-9-ethylcarbazole (AEC) and fast blue BB salt serve as substrates for the peroxidase and the alkaline phosphatase, respectively. The antisera and the enzyme complexes raised in different animals enable the performance of three parallel incubation steps. The staining procedure requires three and a half hours altogether. This method proved to be highly discriminative and rather insensitive to interference by various artifacts.

Concanavalin A (Con A) acceptors have been demonstrated in large differentiated neurons in a previous paper. In order to elucidate the correlation between Con A binding in normal and neoplastic neurons and lectin binding dependence upon the differentiation grade, 26 tumours of the neuronal series were examined using formalin fixed and paraffin embedded biopsy specimen. The neoplasms included 3 gangliocytomas, 7 gangliogliomas, 1 central neuroblastoma, 11 medulloblastomas, 2 retinoblastomas, and 2 sympathicoblastomas. Well differentiated neurons in gangliocytomas and gangliogliomas expressed a high intracytoplasmic Con A acceptor density comparable to the feature in large non-neoplastic neurons. Less differentiated neurons and neuroblasts showed a weak perinuclear fine granular binding or an absolute lack of binding molecules, respectively. Our results suggest that in a variety of tumours, Concanavalin A receptor density in neurons depends upon the degree of differentiation of the cell. Well differentiated cells have a higher density than poorly differentiated neoplastic neurons.

Clinical details of two cases of arteriovenous angioma of the vein of Galen are presented. In one case a diffuse meningo-cerebral angiodysplasia was found at necropsy. Due to a large arteriovenous shunt both cases became apparent in the neonatal period by progressive and fatal heart failure as the main clinical feature. Increased head circumference and a loud cranial bruit suggested the final diagnosis. Improvement of diagnostic work-up by computerized axial tomography and two-dimensional ultrasound with less discomfort to the patient is emphasized.

The intermediate filament complement of the spectrum of nerve sheath neoplasms including 12 typical benign schwannomas, 1 ancient schwannoma, 2 cellular schwannomas, 6 neurofibromas and 4 malignant schwannomas was investigated by immunofluorescence microscopy, two dimensional electrophoresis, and immunoblot analysis. Studies were performed on freshly frozen tumor tissue samples; a broad spectrum of antibodies against all classes of intermediate filaments was utilized. Samples were also studied by electron microscopy, and immunohistochemically for S-100 protein and desmoplakins. By immunofluorescence microscopy, all nerve sheath neoplasms revealed intense positivity for vimentin throughout the cytoplasm while 2 benign schwannomas displayed co-expression of vimentin and glial filament proteins. Two-dimensional gel electrophoresis and immunoblot analysis confirmed the presence of vimentin and showed that it was the predominant protein in all tumors. Electrophoretic analysis of the 2 benign schwannomas that immunostained for glial filament proteins confirmed the presence of this protein which was shown to comigrate with a known human control sample. Neither immunofluorescence microscopy nor biochemical analyses revealed cytokeratin polypeptides, neurofilament proteins, desmin, or desmoplakin in any of the tumors. We conclude that while vimentin is the predominant intermediate filament expressed by the entire spectrum of nerve sheath neoplasms, at least occasional benign schwannomas are capable of co-expressing glial filament proteins. It remains to be determined whether the subgroup of nerve sheath neoplasms that co-expresses vimentin and glial filament proteins is otherwise distinguishable from their more frequent counterparts that express vimentin exclusively.

A human oligo-astrocytoma grade II was successfully grown in tissue culture. Using glial fibrillary acidic protein (GFAP) as an astrocytic marker two main cell types could be differentiated: GFAP-positive astrocytes and GFAP-negative oligodendrocytes. After transformation by SV40 about 90% of the tumor cells expressed SV40 T-antigen as detected by indirect immunofluorescence. The percentage of viral capsid (V-)antigen was much lower; it was only found in oligodendrocytes. Six passages after transformation the oligodendrocytes were eliminated due to lytic viral infection. By double immunofluorescence with anti-GFAP as a cell marker and anti-T as a viral marker the remaining cell type was identified as transformed astrocytes. These data suggest a different susceptibility of oligodendrocytes and astrocytes, respectively, to transformation by SV40. While the oligodendrocytes permit the production of infectious virus, the astrocytes are more sensitive to transformation. The evident correlation to human progressive multifocal leukoencephalopathy will be discussed.

Multiple sclerosis (MS) is one of the most common diseases of the central nervous system. Up to now, there is no pathognomonic test to ascertain the diagnosis and in 10 to 15% of MS cases there are problems in differential diagnosis. We report 15 bioptically diagnosed MS cases with atypical clinical, C.S.F. and neuroradiological findings. In each case the diagnosis of MS was made by CT/MRI-stereotactic brain biopsy. Neoplastic and other non-tumorous lesions could be excluded. Indications for and significance of stereotactic brain biopsy in atypical cases of MS are discussed.

Twenty non-neoplastic parotid glands (removed during neck dissection for regional tumours) were examined for cellular and subcellular binding sites of Ulex europaeus-lectin I (UEA-I), a lectin reported to be specific for alpha-L-fucose. For light microscopy, an extended peroxidase-antiperoxidase method was applied; for the evaluation of the subcellular localization of bound lectin, three of these glands were examined following immunocryoultramicrotomy and staining by the protein A-gold technique. In addition to the known cytoplasmic affinity of UEA-I for capillary endothelium, acinar cells bound the lectin within the cytoplasmic compartment; the number and distribution of stained acinar cells varied among individuals. Furthermore, cytomembrane-bound labelling that occurred most markedly at the luminar surface was observed in striated-duct epithelium. Using the electron microscope, protein A-gold particles were seen in zymogen granules and in Golgi cisternae of serous acinar cells; primary saliva secreted in the lumina exhibited strong labelling; serous acinar cells had binding sites on their cell membranes, striated-duct epithelium had binding sites on its surface membrane and in the vicinity of apical vesicles. Our results show that UEA-I is a useful tool for the study of the structure and functional states of the parotid gland epithelium and its associated pathological alterations.

The purpose of our study was to investigate the value of cytokeratin antibodies for identifying bone marrow involvement in breast cancer patients who showed no evidence of distant metastases using noninvasive tumor staging procedures. Bone marrow for histological (biopsy) and immunocytochemical (aspiration) evaluation was obtained from the anterior iliac crest from 50 unselected consecutive women during surgical treatment of the primary tumor. The histological examination was done on nondecalcified bone sections. The immunocytochemical studies were carried out on interface smears of the bone marrow aspirates. For staining, cytokeratin antibodies (PKK 1) and the immune alkaline phosphatase method was used. Cytokeratin-positive cells were found in 4 of the 50 cases (8%). Of those 4 patients, however, 2 also showed evidence of neoplastic bone marrow infiltration histologically. We thus were able to prove that immunocytochemistry on aspirates is superior to conventional histology in identifying tumor in bone marrow. Nonetheless, our results clearly fell below the rate found in previous studies where epithelial membrane antigen antibodies were used.

A malignant fibrous mesothelioma is reported in a man of 70, arising from the left pleura with widespread metastases in the regional lymph nodes, diaphragm, chest wall, adrenal glands, and brain. Asbestos bodies were not found. Histologically, the primary tumor consisted of interlacing bundles of spindle-shaped malignant cells with a considerable number of mitoses. In the brain two large metastases occurred. Macroscopically, the occipital metastasis looked like an intracranial hemorrhage. Microscopically, the metastases mimicked the pattern of a glioblastoma multiforme. The present case is discussed against the back-ground of the pertinent literature.

We describe two novel monoclonal antibodies specific for glial filament protein (GFP), i.e., GF12.23 and GF12.24 (both IgG2a]. These cross-react over a broad range of species with epitopes located in the alpha-helical rod domain typical of all intermediate filament (IF) proteins. These monoclonal antibodies were used, in conjunction with other monoclonal GFP antibodies, rabbit antiserum to GFP, and various antibodies to other cytoskeletal proteins, to examine the occurrence of GFP in cells outside of the central nervous system of rodents, cows, and humans. We detected some scattered GFP-containing cells in the neural sheaths in some species but not in others, and we obtained different results when comparing the rabbit antisera with the monoclonal GFP antibodies. In the enteric glia of rats, we observed GFP-positive cells with all of the antibodies used, whereas in human intestine, the various monoclonal antibodies showed no reaction with any intestinal cells. Similarly, no GFP was detected in surface cells of the lens of cows and rats using any of the GFP antibodies, whereas some reaction was seen in murine lens tissue. We were also unable to detect GFP-positive cells in human, bovine, or rat liver with any of the monoclonal antibodies, which is in contrast to the reactivity of the rabbit GFP antisera with some stellate perisinusoidal cells of rat but not bovine or human liver. The possible reasons for the discrepancies between the different species and the different antibody preparations used are discussed. In addition, using double-label immunofluorescence microscopy, we showed that normal human parotid glands contain a certain type of epithelial cell that co-expresses cytokeratins and desmosomal proteins with GFP. The histological distribution of these GFP-positive cells suggests that they represent a subset of the myoepithelial cells present in this tissue. Cells co-expressing cytokeratins and GFP - in some cases, apparently together with vimentin as the third IF protein present - were also identified in tumors derived from this salivary-gland epithelium, i.e., pleomorphic adenomas, in which GFP-positive cells were relatively frequent in the myxoid and chondroid components, thus confirming the work of other investigators. Possible implications for the concept of histogenesis of these tumor cells are discussed, as are possible mechanisms resulting in the co-expression of IF proteins.

We have correlated the light-microscopic features in the unmyelinated hypothalamus with gonadal atrophy in 15 women of 30-111 years of age and in 7 men between 29 and 82 years. In the postmenstrual cases there is a distinct concordance of gonadal atrophy and the manifestation of nucleolar changes (augmentation, multiplication and vacuolization) in many nerve cells of the arcuate and subventricular nuclei. In younger, still fertile women this nucleolar finding was seen only rarely and sporadically, was limited to the arcuate nucleus and was absent in the subventricular nucleus. We interpret this nucleolar finding as a feedback effect. In man, too, this coincidence is obvious with age and in gonadal atrophy, with fewer nucleolar changes in old age than are seen in women. This difference is probably caused by a more rapid drop of the estradiol than of the testosterone level. - The hypertrophy of the subventricular nucleus (Sheehan and Kovacs) was also observed in our postmenstrual cases.

The case-history of a child with von Recklinghausen disease is described: The patient suffered the following tumors: Olfactory nerv meningeoma, optic nerv glioma, acoustic nerv neurinoma, intraventricular meningeomas, intraspinal ependymoma and peripheral neurinomas. The pathogenesis (neurocristopathy) and aetiology are discussed.

The distribution of selective cytokeratin polypeptides, vimentin, and glial fibrillary protein (GFP) in 5 human cystadenolymphomas of the parotid gland was compared with normal human parotid (n = 5) and submandibular (n = 4) glands using a panel of monoclonal antibodies against diverse and selective cytokeratin polypeptides, vimentin and glial fibrillary protein (GFP). A biotinstreptavidin method was used on cryostat sections. The immunocytochemical finding of identical cytokeratin polypeptides Nos. 7, 8, 18 and 19 and basal cells selectively labeled by the monoclonal antibody KS 8.58, in both the epithelial part of the cystadenolymphomas and in the duct epithelium of the parotid gland, confirms the hypothesis that the epithelial compartment of cystadenolymphomas is derived from the duct system. The triple expression of cytokeratin, vimentin and GFP in myoepithelial cells of the parotid gland is discussed.